High Progesterone Levels Research Articles

Abstract 096: Progesterone Upregulates Endothelial Mineralocorticoid Receptor Expression Which Predisposes Female Mice to Obesity-Induced Endothelial Dysfunction

Compelling evidence indicates a higher efficacy of mineralocorticoid receptor (MR) blockade for the treatment of cardiovascular disease in females with obesity and diabetes than in males, however, the origin of this sex-specific effect is unknown. We have shown that leptin induces endothelial dysfunction in obese female mice via aldosterone-dependent activation of MR and that only female mice develop endothelial dysfunction (vasorelaxation to acetylcholine) in response to aldosterone ex vivo . Therefore, we hypothesized that females express higher endothelial MR (ECMR) expression than males which predisposes females to obesity-associated endothelial dysfunction. RT-PCR analysis in isolated aortic endothelial cells of Balb/C mice revealed a higher NR3C2 (MR gene) expression in females compared to males (2.9±0.5-fold from male, P<0.05), however, no such difference was observed in non-endothelial cells. Similarly, human adipose tissue endothelial cells exhibited higher ECMR mRNA expression than males (2.1±0.1 fold from male). Female sex-hormone suppression (ovariectomy) decreased ECMR expression in female mice (-0.8±0.2-fold from sham), which was restored by progesterone supplementation (-0.1±0.1-fold from sham). NR3C2 mRNA gradually increased with progesterone in diestrous (1.6±0.1-fold from estrous) phase and increased further in pregnancy day 16 (9.2±0.2-fold from estrous). Furthermore, progesterone dose-dependently increased ECMR protein expression in human endothelial cells in vitro (P<0.05). Increases in ECMR associated with higher progesterone levels in diestrus and pregnant females were associated with an increased sensitivity to leptin-induced endothelial dysfunction in mice. In parallel, while leptin induced endothelial dysfunction in intact ECMR female mice (P<0.05), specific deletion of MR in endothelial cells protected female mice from leptin-induced endothelial dysfunction. These data indicate that progesterone drives the sex-difference in the levels of ECMR expression and predisposes female mice to leptin-induced endothelial dysfunction. In addition, these data provide a rational for the higher efficacy of MR blockade in obese and diabetic women suffering from cardiovascular disease.

Effects of dyslipidemia on in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) pregnancy outcome in patients with polycystic ovary syndrome(PCOS)

To investigate the impact of dyslipidemia on IVF/ICSI pregnancy outcome in patients with PCOS. Retrospective cohort study. From July 2013 to March 2016,468 cases of PCOS patients with antagonist protocol in in-vitro fertilization and embryo transfer were included using CCRM database of our center,cycles were divided into dyslipidemia group(DG,n=108) and normol blood lipids group(NG,n=360) according to the serum cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low density lipoprotein (LDL) levels.The general condition and clinical outcomes of the two groups were analyzed retrospectively, including the implantation rate(IR), clinical pregnancy rate(CPR), and live birth rate(LBR), etc. Besides,stratified analysis and multivariate logistic regression analysis were used to correct the impact of body mass index(BMI). 1.Age,years of infertility, basic hormone levels and other basic data of two groups were similar (P>0.05), but BMI of DG was significantly higher than NG(25.01±2.96 vs. 23.11±3.05 , P<0.001); 2.The high quality embryo rate,endometrial thickness,progesterone and LH levels on the day of HCG injection,severe hyperstimulation rate and miscarriage rate in two groups falied to exhibit remarkable difference(P>0.05). However, the number of oocytes retrieved,estradiol(E2) level on the day of HCG injection,IR,biochemical pregnancy rate(BPR),CPR and LBR in DG were significantly lower than NG(10.24±5.06 vs. 11.48±5.62, 15824.53±8925.22 vs. 18985.61±10751.99, 31.03% vs. 52.97%, 57.14% vs. 77.68%, 40.00% vs. 70.54%, 25.71% vs.59.82%,P<0.05), the dose of Gn and days of stimulation were significantly higher compared to NG(1778.94±797.20 vs. 1358.84±510.01, 10.83±2.43 vs. 9.76±1.90,P<0.05). 3.Stratified analysis showed that no matter in BMI < 24 or BMI≥24 group, the dose of Gn and days of stimulation were significantly higher in DG than NG (P<0.05).However,the number of oocytes retrieved, E2 level on the day of HCG injection had obvious downtrend, and the difference was statistically significant (P <0.05) in BMI≥24 group.Even after adjustment of BMI, dyslipidemia still had a negative impact on IR,BPR,CPR and LBR (OR 0.377, 0.382, 0.250, 0.233,P <0.05).4.Further analysis of the different components of blood lipids in the clinical pregnancy group and unobtained pregnancy group revealed that TG in the non-pregnant group was significantly higher (1.49±0.84 vs. 1.24±0.65,P=0.045), Logistic regression analysis also showed that the increase of TG levels was negatively correlated with the CPR in PCOS patients(OR 0.274,P=0.041). In patients with PCOS,patients combined with dyslipidemia have a higher BMI,and dyslipidemia increases the dosage of Gn, reduces the IR,CPR and LBR, especially the increase of TG level,which has adverse effects on IVF/ICSI outcome.A reasonable control of blood lipid level and weight may help to improve the pregnancy outcome in patients with PCOS.

Not one hormone or another: Aggression differentially affects progesterone and testosterone in a South American ovenbird

Behaviors such as territorial interactions among individuals can modulate vertebrate physiology and vice versa. Testosterone has been pointed out as a key hormone that can be rapidly affected by aggressive interactions. However, experimental evidence for such a link is mixed. In addition, behaviors can elicit changes in multiple hormones, which in turn have the potential to synergistically feedback to behavior. For example testosterone and progesterone can act interdependently in modulating male behavior. However, if aggression can affect progesterone levels in males remain unknown and – to the best of our knowledge – no one has yet tackled if and how aggressive behavior simultaneously affects testosterone and progesterone in free-living animals. We addressed these questions by performing simulated territorial intrusion experiments measuring both hormones and their ratio in male rufous horneros (Aves, Furnarius rufus) during the mating and parental care periods. Aggression affected testosterone and progesterone differentially depending on the period of testing: challenged birds had higher levels of progesterone during the mating period and lower levels of testosterone during parental care compared to controls. Challenged individuals had similar progesterone to testosterone ratios during both periods and these ratios were higher than those of control birds. In summary, territorial aggression triggered hormonal pathways differentially depending on the stage of the breeding cycle, but equally altered their ratio independent of it. Our results indicate that multiple related hormones could be playing a role rather than each hormone alone in response to social interactions.

The Neuromodulatory Effects of Sex Hormones on Functional Cerebral Asymmetries and Cognitive Control

Abstract. Nearly 20 years ago, Hausmann and Güntürkün (2000a, 2000b) published a review article in the Journal of Neuropsychology/Zeitschrift für Neuropsychologie on the influences of sex hormones on functional cerebral asymmetries (FCAs). They further presented a neuroendocrinological model (Hausmann &amp; Güntürkün, 2000c) that could potentially explain how sex hormones modulate FCAs. Their model proposed that high levels of progesterone reduce the synaptic efficiency of cortico-cortical transmission, leading to a reduction of FCAs. However, empirical data testing their hypothesis directly were missing. Using various approaches, we have now gathered behavioral, electrophysiological, and neuroimaging data that partly support the original idea, while also pointing toward estradiol-modulating FCAs. The current review provides an update on this fascinating topic and briefly explores clinical applications.

The randomised controlled trial of micronised progesterone and dydrogesterone (TRoMaD) for threatened miscarriage

There has not been conclusive evidence in literature on the efficacy of progestogen in the treatment of threatened miscarriage, although some studies showed benefits. In our centre, threatened miscarriage is treated with either micronised progesterone (MP) or dydrogesterone (DYD). ObjectiveThe aim of this study is to compare clinical outcomes of miscarriage, extent of vaginal bleeding at follow-up and side effects between treatment groups. Study designThis study was a prospective parallel-group, open-label, randomized controlled trial. 141 women presenting with threatened miscarriage were randomised to either MP or DYD of which 118 were included in the analysis. Baseline maternal demographics and serum progesterone levels were collected at presentation. Post-treatment bleeding pattern and self-reported side effects were recorded at the follow-up visit (on day 4–10 of treatment). The occurrence of spontaneous miscarriage was ascertained at week 16 of gestation. ResultsThe population with miscarriage and resolution of bleeding were not statistically different between MP and DYD groups. A significantly higher percentage of women treated with MP reported drowsiness (p = 0.003). After stratification into low and high serum progesterone levels, a significantly higher miscarriage rate was found in the low progesterone group, regardless of treatment type. ConclusionIn conclusion, extent of bleeding at day 4–10 and subsequent miscarriage rates were comparable between MP and DYD groups. However, fewer patients treated with DYD reported drowsiness and giddiness. The finding of significantly higher miscarriage rates in women with low progesterone levels despite treatment is an important factor to consider in counselling and prognosticating pregnancy outcomes.

"Luteal Analgesia": Progesterone Dissociates Pain Intensity and Unpleasantness by Influencing Emotion Regulation Networks.

Background: Pregnancy-induced analgesia is known to occur in association with the very high levels of estradiol and progesterone circulating during pregnancy. In women with natural ovulatory menstrual cycles, more modest rises in these hormones occur on a monthly basis. We therefore hypothesized that the high estradiol high progesterone state indicative of ovulation would be associated with a reduction in the pain experience.Methods: We used fMRI and a noxious thermal stimulus to explore the relationship between sex steroid hormones and the pain experience. Specifically, we assessed the relationship with stimulus-related activity in key regions of networks involved in emotion regulation, and functional connectivity between these regions.Results: We demonstrate that physiologically high progesterone levels are associated with a reduction in the affective component of the pain experience and a dissociation between pain intensity and unpleasantness. This dissociation is related to decreased functional connectivity between the inferior frontal gyrus and amygdala. Moreover, we have shown that in the pre-ovulatory state, the traditionally “male” sex hormone, testosterone, is the strongest hormonal regulator of pain-related activity and connectivity within the emotional regulation network. However, following ovulation the traditionally “female” sex hormones, estradiol and progesterone, appear to dominate.Conclusions: We propose that a phenomenon of “luteal analgesia” exists with potential reproductive advantages.

Freeze-all strategy in IVF/ICSI cycles: an update on clinical utility.

Over the years concerns have arisen about possible adverse effects associated with controlled ovarian stimulation (COS) as regards not only the endometrium, but also on obstetrical and perinatal outcomes in pregnancies after fresh embryo transfer (ET) during in-vitro fertilization (IVF) treatment. The improvements in cryopreservation techniques associated with the possible impairment in endometrial receptivity due to the supra-physiologic hormonal levels observed during conventional COS have increased the implementation of the so-called "freeze-all" policy. With this strategy, the entire cohort of embryos is cryopreserved to be transferred to the uterus in subsequent cycles in a more physiological environment, avoiding the supra-physiologic hormonal levels observed during COS. The initial studies showed that this strategy could be beneficial for subgroups of patients, however, the freeze-all policy is being more and more frequently used for all patient categories. Unfortunately, currently, no clinical data support this widespread use of the freeze-all strategy. Based on available trials, it seems justified to implement the strategy in patients with risk of ovarian hyperstimulation syndrome, hyper-responders and when performing preimplantation genetic testing for aneuploidy in blastocyst stage. Therefore, all the other indications, such as implantation failure, high progesterone levels on the trigger day, advanced maternal age, and endometriosis, still lack the evidence to support routine use of the freeze-all policy.

Aggression in Women: Behavior, Brain and Hormones.

We review the literature on aggression in women with an emphasis on laboratory experimentation and hormonal and brain mechanisms. Women tend to engage in more indirect forms of aggression (e.g., spreading rumors) than other types of aggression. In laboratory studies, women are less aggressive than men, but provocation attenuates this difference. In the real world, women are just as likely to aggress against their romantic partner as men are, but men cause more serious physical and psychological harm. A very small minority of women are also sexually violent. Women are susceptible to alcohol-related aggression, but this type of aggression may be limited to women high in trait aggression. Fear of being harmed is a robust inhibitor of direct aggression in women. There are too few studies and most are underpowered to detect unique neural mechanisms associated with aggression in women. Testosterone shows the same small, positive relationship with aggression in women as in men. The role of cortisol is unclear, although some evidence suggests that women who are high in testosterone and low in cortisol show heightened aggression. Under some circumstances, oxytocin may increase aggression by enhancing reactivity to provocation and simultaneously lowering perceptions of danger that normally inhibit many women from retaliating. There is some evidence that high levels of estradiol and progesterone are associated with low levels of aggression. We highlight that more gender-specific theory-driven hypothesis testing is needed with larger samples of women and aggression paradigms relevant to women.

Evaluation the relationship between serum progesterone level and pain perception after cesarean delivery

Introduction: Cesarean delivery is the most common surgery in obstetrics, and pain relief after cesarean section is an important concern for obstetricians and their patients.Objective: The aim of this study was to evaluate the relationship between serum progesterone level and pain perception after cesarean delivery.Method: The study was performed as a prospective cohort study on 166 pregnant women who were candidates for elective cesarean delivery due to previous cesarean section. Before surgery, serum progesterone level was measured. Pain score of women was evaluated 4, 8, 12, and 24 h after surgery using visual analog scale (VAS) score, and correlation between progesterone level and pain was evaluated.Results: The median value of serum progesterone was 119.45 ng/ml. Mean pain score in hours 4, 8, 12, and 24 were 6.80 ± 2.11, 5.31 ± 1.48, 3.89 ± 1.68, and 2.30 ± 1.26, respectively. The women were divided according to mean progesterone level of 119.45 ng/ml into two groups of high progesterone level (≥119.45) and low progesterone level (<119.45), and the pain score was evaluated in different times (hour 4, 8, 12, and 24) for both levels of progesterone. The mean pain score in the 4, 8, 12, and 24 h were significantly lower in high progesterone group (progesterone level ≥119.45). The number of women with low pain score (less than five) in hours 12 and 24 was significantly higher in high progesterone level group. With increasing BMI, progesterone level was lower and women with higher BMI, had a higher pain score in hours 4, 8, 12, and 24, while women with lower BMI had a lower pain score during the same hours. (p = .004, r = 0.223; p = .004, r = 0.223; p = .039, r = 0.160; and p = .007, r = 0.207). Progesterone level and BMI (p = .025, r = − 0.174), and progesterone level and pain score in hours 4, 8, 12, and 24 (p = .000, r = − 0.324; p = .000, r = − 0.474; p = .000, r = − 0.329; and p = .000, r = − 0.417, respectively) showed a negative significant correlation. Putting three variables of age, gestational age, and BMI in a multiple regression model, progesterone level showed significant negative correlation with the pain score in hour 4 (p = .000, r = − 0.305), hour 8 (p = .000, r = − 0.461), hour 12 (p = .000, r = − 0.328), and hour 24 (p = .000, r = − 0.409).Conclusions: Serum progesterone level showed a negative correlation with the pain score after cesarean section.

Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by large variability in disease severity, that is only partly explained by (epi)genetic factors. Clinical observations and recent in vitro work suggest a protective effect of estrogens in FSHD. The aims of this study were to assess whether the lifetime endogenous estrogen exposure contributes to the variability in disease severity in female patients, and whether female patients experience changes in disease progression during periods of hormonal changes. We calculated the lifetime endogenous estrogen exposure by subtracting periods with high progesterone levels (in which estrogens are counteracted) from the reproductive life span. Multiple linear regression in 85 patients did not show a contribution of the lifetime endogenous estrogen exposure to disease severity (B = 0.063, P-value = 0.517, ΔR2 = 0.003). The majority of women reported an unchanged rate of disease progression through periods of hormonal changes, like menarche, pregnancy or menopause. Women that noticed differences reported accelerations as well as decelerations. These results indicate that differences in estrogen exposure do not have a clinically relevant modifying effect on disease severity. However, a clinically relevant protective effect of greater differences in estrogen levels, or a protective effect caused by a more complex interplay with other reproductive hormones, cannot be ruled out.

High progesterone levels on the day of HCG administration do not affect the embryo quality and the reproductive outcomes of frozen embryo transfers.

The aim of this study was to evaluate the impact of pre- mature progesterone rise on the day of human chorionic gonadotropin (hCG) administration on the outcome of in vitro fertilization (IVF) of frozen embryo transfer (FET) cycles using cleavage-stage embryos. This was a retrospective, cohort study of 131 ovarian stimulation cycles followed by cleavage-stage frozen embryo transfers. The first group consisted of women undergoing FET due to premature luteinization during controlled ovarian stimulation (n = 56, P ≥1.2 ng/ml). The controls were represented by women undergoing FET not complicated by high progesterone levels at induction (n = 75, P < 1.2 ng/ml). For both groups, the progesterone was measured on the day of hCG administration and the fertilization rate, cleavage rate, implantation rate, clinical pregnancy rate, ongoing pregnancy rate and Top-Quality Embryos (TQE) rates were compared. The increase of progesterone in patients of the Group A had no significant effects on the number of oocytes retrieved or available for the insemination. The fertilization rate, cleavage rate and implantation rates, as well as the clinical pregnancy rate and ongoing pregnancy were very similar in both study groups. The analysis of TQE rates between the two groups indicated a roughly comparable result. The results of this study showed that progesterone elevation on the day of hCG administration did not affect the outcomes of IVF with frozen embryos at cleavage stage. This study therefore confirms that for patients with high progesterone levels the right way to obtain a healthy pregnancy should be to delay the embryo transfer at a successive FET cycle, not associated with the ovarian stimulation.

Is ovulation induction with letrozole in breast cancer patients still safe even if it could increase progesterone levels?

Very high progesterone levels (mean 186.6 ± 43.6 ng/mL) during the luteal phase were found in a small study of breast cancers patients undergoing controlled ovarian stimulation (COS) with letrozole plus recombinant FSH. Results highlight the need to further evaluate this in larger series. While waiting, the clinical significance of high progesterone levels can be drawn from epidemiological and experimental data here reviewed in order to give reassurance to the clinician involved in fertility preservation. If the progesterone increase will be confirmed, epidemiological and experimental data do not seem to indicate a detrimental effect or they could even be protective. As this possible rise of levels is a very short event in the very long lasting and multifactorial breast carcinogenesis, it is unlikely that it will significantly influence breast cancer prognosis.

The Role of Estrogen and Progesterone Hormone on Vaginal Cytology in Bitch

The aim of the present study was to determine the stages of the reproductive cycle of the bitch by using the exfoliative vaginal cytology technique and its relationship with hormonal level. A total of 12 bitches (n=12) were selected and vaginal cytology along with hormonal estimation was done to identify the different stages of the reproductive cycle. The vaginal samples were collected as per the cotton swab technique and stained with Leishman stain and examined microscopically for differential count of exfoliated vaginal epithelial cells. On the same day blood samples were also collected aseptically for hormonal estimation. The percentage of parabasal cell, intermediate cell and superficial cells were 7.04±0.28, 22.33±0.28, and 62.32±0.28 in proestrus; 0.56±0.03, 5.68±0.03 and 92.29±0.03in estrus and 32.56±0.28, 35.08±0.28 and 12.83±0.28 in diestrus respectively. Vaginal smears were characterized by presence of massive numbers of erythrocytes and disappearance of neutrophils in proestrus, clear background of smear and absence of neutrophils with scanty erythrocytes in estrus, infiltration of neutrophils and dirty background in diestrus. The estrogen level (29.50 ±0.28) was statistically high during proestrus and highest progesterone level (39.50 ±0.28) during diestrus. On conclusion, hormonal changes in different stages of reproductive cycle presented mainly by the effect of elevated estrogen hormone that associated with increase in superficial cells count and cornification, with reduction in neutrophil and parabasal cell in estrus and Progesterone hormone showed increased towards diestrus level with increasing intermediate cells.

An Interesting Case of Acute Intermittent Porphyria Precipitated During Premenstrual Phase

Acute intermittent porphyria is one of the rare, autosomal dominant, hereditary hepatic porphyria due to deficiency of enzyme Hydroxyl Methyl Bilane synthase (HMB synthase) in the haem synthesis pathway. The condition is characterized by acute abdominal pain and neuropsychiatric manifestations. One of the precipitating causes of AIP is menstruation due to high levels of progesterone. We report an interesting case of AIP precipitated during each cycle of menstruation.

The impact of high progesterone levels on the day of HCG administration in assisted human reproduction treatments.

ObjectiveProgesterone is a steroid hormone that acts on the endometrium. It is known for producing physical and mood-related side effects. Few studies have looked into how progesterone levels affect embryo development and quality. This study aimed to find a cutoff level for serum progesterone on the day of HCG administration from which embryo quality is impaired.MethodsThe study included 145 cycles, from which 885 oocytes and 613 embryos were obtained. All patients had their serum progesterone levels measured on the day of HCG administration. Data sets were collected from patient medical records. The chi-square test was used to assess qualitative variables and the Mann-Whitney test to evaluate quantitative variables.ResultsStatistical analysis revealed that serum progesterone levels and reproductive variables were not significantly associated. In regards to oocyte maturity, however, when progesterone levels were greater than 1.3 ng/mL the probability of oocytes being immature increased by 12.7%. The fragmentation rate of embryos categorized as "top quality" in D3 increased proportionately to increases in progesterone levels (12.23%).ConclusionHigh progesterone levels appeared to be correlated with increased embryo fragmentation rates, but high serum levels of the hormone on the day of HCG administration had no impact on reproductive variables and were not associated with impaired embryo development.

Impact of endogenous progesterone on reactivity to yohimbine and cocaine cues in cocaine-dependent women

Background and objectiveData from clinical and preclinical models of relapse suggest that progesterone attenuates cocaine-seeking behavior. In a recent study, we found that cocaine-dependent women reported greater subjective responses to cues that were preceded by a stressor than cocaine-dependent men. The objective of this study was to examine the impact of endogenous progesterone on the subjective and endocrine responses to a drug-paired cue that was preceded by a stressor in cocaine-dependent women. MethodsCocaine-dependent women with low (<4ng/ml; n=16) and high (≥4ng/ml; n=9) plasma progesterone levels received either the alpha-2 adrenergic receptor antagonist yohimbine (21.6mg) or placebo before each of two cocaine-cue exposure sessions. Participants were tested under both conditions in a counterbalanced, double-blind fashion. Data were collected after study drug administration, immediately and at 5, 30, and 60min after the cue. ResultsThe anxiety response to the cue was differentially modified by progesterone levels under the two administration conditions (condition×progesterone level interaction, F1,23=9.8, p=0.005). Progesterone levels also modified the craving response to the cue differently under the placebo condition as compared to the yohimbine condition (condition×progesterone level interaction, F1,23=13.9, p=0.001). In both cases, high progesterone levels attenuated craving and anxiety response to the cue following yohimbine administration. There was no effect of progesterone levels on salivary cortisol or dehydroepiandrosterone under the placebo condition or under the yohimbine condition. ConclusionsThese preliminary data suggest that high levels of endogenous progesterone attenuate subjective responses to drug-cues that are preceded by a stressor. Importantly, these data support a growing literature demonstrating the protective effects of progesterone on the vulnerability to cocaine relapse in women.

Progesterone level significance in agonist versus antagonist protocols

Abstract Objective to evaluate the impact of serum progesterone level on the clinical outcome across agonist & antagonist protocols. Design retrospective cohort study. Setting IVF unit at Prince Sultan Military Medical City, Riyadh, KSA. Material & Methods A total of 943 cycles were included in the analysis, 605 long agonist protocol cycles, 227 antagonist protocol cycles & 101 short agonist protocol cycles reaching the stage of embryo transfer between November 2012 and March 2015. Main outcome clinical pregnancy and miscarriage rates. Results Number of retrieved, mature and fertilized oocytes, plus transferred embryos were lowest in the short protocol. Clinical pregnancy rate was the lowest in the short protocol and miscarriage rate was similar in all protocols. Setting progesterone cut off level of >1.5 nmol/L in the agonist cycles, high progesterone groups did not show difference in clinical pregnancy or miscarriage rates. In the short protocol, the group with high progesterone level had higher number of frozen embryos. In long protocol, high progesterone level group showed higher number of fertilized oocytes. A level of >2 nmol/L was set in the antagonist protocol. High progesterone group had lower clinical pregnancy rate and similar miscarriage rate, despite having higher number of fertilized oocytes and better quality of embryos. Conclusion high progesterone level did not affect clinical pregnancy or miscarriage rates in all protocols except in the antagonist protocol where it affected the clinical pregnancy rate adversely.

Leptin siRNA promotes ovarian granulosa cell apoptosis and affects steroidogenesis by increasing NPY2 receptor expression

Leptin has been found to be involved in the ovarian granulosa cell apoptosis and steroidogenesis. Loss of neuropeptide Y (NPY) can correct the obesity syndrome of mutant mice lacking of leptin (ob/ob). However, the association of NPY and leptin in ovarian granulosa cells and ovarian steroidogenesis has not been investigated. Here, C57BL/6J ob/ob mice and C57BL/6J (control) mice were intraperitoneally injected with PBS, leptin (0.4μg/g bodyweight) or BIIE0246 (NPY2 receptor [NPY2R] antagonist, 30μg/kg bodyweight) every day for 15days. We found that NPY2R mRNA expression in mouse ovary was suppressed by leptin treatment, but increased by leptin deficiency. Leptin or BIIE0246 treatment significantly increased E2, but notably decreased progesterone in both mice. A lower level of E2 and a higher level of progesterone was observed in ob/ob mice than in control mice. Further, we then knocked down leptin expression in human ovarian granulosa cells by siRNA transfection and treated the cells with DMSO or BIIE0246. In vitro experiments confirmed the findings in mice. siLeptin treatment decreased the secretion of E2, anti-Mullerian hormone (AMH), insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β, and the cell proliferation, but increased the secretion of progesterone and cell apoptosis. Western blotting analysis of PCNA, Bcl-2 and Bax confirmed the results of cell proliferation and apoptosis. Activation of JAK2 and STAT3 was also suppressed by knocking down leptin. All the effects of siLeptin on ovarian granulosa cells were partially reversed by BIIE0246. In conclusion, knockdown of leptin significantly affected ovarian steroidogenesis and ovarian function through NPY. siLeptin transfection impaired the activation of JAK2/STAT3 and contributed to ovarian granulosa cell apoptosis partially through up-regulating NPY2R expression.

Effects of high progesterone level on the day of human chorionic gonadotrophin administration in in vitro fertilization cycles on epigenetic modification of endometrium in the peri-implantation period

To investigate the effects of high P level on the day of hCG administration in IVF cycles on epigenetic modifications of endometrium in the peri-implantation period. Retrospective study. University assisted reproductive unit. Forty patients were recruited: 20 women with high P levels were compared with 20 women with normal P levels. Endometrial tissues were collected 7days after hCG administration in women with normal or high P levels on the dayof hCG administration. Immunohistochemical staining of DNA methylation (5-methylcytosine, 5-mC), histone methylation (H3K4me2/3, H3K9me2, H3K27me3), and histone acetylation (H3K4ac, H3K9ac) was performed. A semiquantitative analysis was performed in the luminal epithelium, glandular epithelium, and stroma, separately. Correlations between P, estrogen levels, and epigenetic markers were compared. In luminal epithelium, the expression of H3K9me2 in the high P group was significantly higher than that in the normal Pgroup. In glandular epithelium, the expression of 5-mC, H3K9me2, and H3K9ac in the high P group was significantly higher than that in the normal P group. In stroma, the expression of H3K27me3 in the high P group was significantly higher than that in the normal P group. Expression of 5-mC in glandular epithelium, H3k9me2 in glandular and luminal epithelium, and H3K27me3 in stroma was significantly correlated with P levels. H3k9me2 in glandular epithelium was significantly correlated with estrogen levels. High P level on the day of hCG administration in IVF cycles affects epigenetic modifications in three compartments of endometrium in the peri-implantation period. The epigenetic markers' expression was mainly correlated with P level. The altered epigenetic modification status in the endometrium may disrupt the endometrial receptivity in women with high P on the day of hCG administration.

Impact of Physical Training on Sex Hormones and Their Receptors During N-Methyl-N-nitrosourea-induced Carcinogenesis in Rats.

The risk of breast cancer is related to duration of exposure to sex hormones, especially estrogen. The aim of this study was to assess the impact of physical training (PT) on estrogen and progesterone levels and expression of their receptors during carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in rats. Fifty female Sprague-Dawley rats were intraperitoneally administered MNU and divided into four groups: low-, moderate-, and high-intensity PT, and no PT (control). Plasma levels of sex hormones and tissue expression of their receptors were quantified and statistically analyzed. In the group of rats subjected to PT, a significantly higher progesterone level was observed. The highest progesterone level was noted in the low-intensity PT group. An increase in apoptosis of MNU-induced tumor cells was also demonstrated in the PT groups. PT stimulates apoptosis of tumor cells without an increase in their proliferative activity. The increase in apoptosis of tumor cells correlates positively with the progesterone level.